1 The presence of b 3 -adrenoceptors and the low a nity state of the b 1 -adrenoceptor (formerlỳ putative b 4 -adrenoceptor') was investigated in ring preparations of rat isolated aorta preconstricted with phenylephrine or prostaglandin F 2a (PGF 2a ). Relaxant responses to isoprenaline, selective b 3 -adrenoceptor agonists (BRL 37344, SR 58611A, CL 316243) and non-conventional partial agonists (CGP 12177A, cyanopindolol, pindolol) were obtained. 2 In phenylephrine-constricted, but not PGF 2a -constricted rings, relaxations to isoprenaline showed a propranolol-resistant component. 3 In phenylephrine-constricted rings, relaxations to BRL 37344 (pEC 50 , 4.64) and SR 58611A (pEC 50 , 4.94) were not antagonized by the selective b 3 -adrenoceptor antagonist SR 59230A (41 mM). CL 316243 (4100 mM) failed to produce relaxation. In PGF 2a -constricted rings only SR 58611A produced relaxation, which was not a ected by SR 59230A (43 mM). 4 Non-conventional partial agonists produced relaxation in phenylephrine-constricted but not PGF 2a -constricted rings. The relaxation to CGP 12177A was una ected by SR 59230A (41 mM) or by CGP 20712A (10 mM), reported to block the low a nity state of the b 1 -adrenoceptor. Abbreviations: DMSO, dimethyl sulphoxide; pEC 50 , negative logarithm of the concentration (M) of relaxant that produces 50% of its maximum response; PG, prostaglandin; R max , %, maximum % relaxation

1 The a 1 -adrenoceptor antagonist properties of the b-adrenoceptor nonconventional partial agonist, CGP 12177A, was investigated in functional assays in rat aorta and in radioligand binding assays in rat cerebral cortical membranes. In addition, binding affinities of other b-adrenoceptor ligands were measured to investigate any correlation between a 1 -adrenoceptor affinity and relaxant potency in phenylephrine-constricted rings. 2 In functional studies, CGP 12177A produced parallel rightward shifts of the phenylephrine CRC with no reduction in the maximum responses. Schild regression analysis gave a straight line with a slope of 0.95 (95% CL: 0.87-1.04), suggesting reversible competitive antagonism, and gave a pK B value of 5.26. In contrast, CGP 12177A (p300 mM) had no effect on contraction induced by the thromboxane-mimetic, U46619. Abbreviations: B max , total number of receptor binding sites; CL, confidence limits; CRC, concentration-response curve; DMSO, dimethyl sulphoxide; E max , maximum response; IC 50 , concentration (M) of competing ligand that inhibits binding of radioligand by 50%; pEC 50 , negative logarithm of the concentration (M) of relaxant that produces 50% of its maximum response; pK B , negative logarithm of the equilibrium dissociation constant, obtained from functional experiments; pK D , negative logarithm of the equilibrium dissociation constant, obtained from saturation experiments; pK i , negative logarithm of the equilibrium dissociation constant, obtained from competition experiments; s.e.m., standard error of the mean

One hundred fifty-six unrelated healthy South Indian subjects were phenotyped according to their ability to metabolize dextromethorphan to its O-demethylated metabolite dextrorphan. Each volunteer was administered 25 mg oral dextromethorphan hydrobromide (19.3 mg dextromethorphan). Urine was collected during an 8-hour period after drug administration and was analyzed for dextromethorphan and dextrorphan by HPLC with fluorescence detection. This analysis was performed with and without previous deconjugation. The log10 (metabolic ratio), calculated as the ratio of dextromethorphan to dextrorphan, was bimodally distributed, and it was inferred that the frequency of occurrence of poor metabolizers of dextromethorphan in South Indian subjects is 3.2%. Phenotype assignment remained the same with both methods of analysis. Furthermore, a fairly good correlation (Spearman rank order correlation coefficient [r(s)] = 0.61; P < .0001) was observed between the log-transformed metabolic ratio derived from both methods.